IgE expression pattern in lung: relation to systemic IgE and asthma phenotypes.
ABSTRACT: BACKGROUND:IgE-mediated responses contribute to allergy and asthma. Little is understood regarding the relationship of tissue IgE to systemic IgE, inflammation or clinical outcomes. OBJECTIVES:To evaluate local IgE expression and cellular inflammation in the proximal and distal lung of normal subjects and subjects with asthma of varying severity and relate those tissue parameters to systemic IgE levels, atopy, lung function, and history of severe exacerbations of asthma. METHODS:Tissue from more than 90 subjects with eosinophilic (SAeo(+)) and noneosinophilic (SAeo(-)) severe asthma, mild asthma and normal subjects were immunostained for IgE, signal-amplifying isoform of IgE receptor (FcepsilonRIbeta) and markers of mast cells, eosinophils, and lymphocytes. Tissue expression of IgE, FcepsilonRIbeta, cellular inflammation, serum IgE, and atopy were compared. Regression models were used to determine the relationship of local and systemic IgE to lung function and severe exacerbations of asthma. RESULTS:Mast cell-bound IgE was present along airways but absent in lung parenchyma. Although the groups were similar in systemic/serum IgE and atopy, local/tissue IgE was highest in SAeo(+) and correlated with eosinophils and lymphocytes (r(s) = 0.52, P < .0001; and r(s) = 0.23, P = .03, respectively). Higher local IgE was associated with better lung function, but also with more severe exacerbations of asthma. CONCLUSION:Local IgE appears to be primarily a component of responses within the mucosal immune compartment and is related to cellular inflammation, lung function, and clinical outcomes in asthma. CLINICAL IMPLICATIONS:Local/airway IgE-related processes rather than systemic markers of atopy may be relevant in determining clinical outcomes in asthma.
Project description:Severe asthma has been associated with severe exacerbations, lower lung function and greater tissue inflammation. Previous studies have suggested that mutations in interleukin-4 receptor alpha (IL4Ralpha) are associated with lower lung function, higher IgE, and a gain in receptor function. However, an effect on exacerbations and tissue inflammation has not been shown.Allelic substitutions in IL4Ralpha are associated with asthma exacerbations, lower lung function, and tissue inflammation, in particular to mast cells and IgE.Two well-characterized cohorts of subjects with severe asthma were analyzed for five single nucleotide polymorphisms (SNPs) in IL4Ralpha. These polymorphisms were compared with the history of severe asthma exacerbations and lung function. In the primary (National Jewish) cohort, these polymorphisms were also compared with endobronchial tissue inflammatory cells and local IgE.In both cohorts, the presence of the minor alleles at E375A and Q551R, which were more common in African Americans, was associated with a history of severe exacerbations and lower lung function. In the National Jewish cohort, the C allele at E375A was associated with higher tissue mast cells and higher levels of IgE bound to mast cells. The significance for most of these associations remained when whites (the larger racial subgroup) were analyzed separately.SNPs in IL4Ralpha, which are more common in African Americans, are associated with severe asthma exacerbations, lower lung function, and increased mast cell-related tissue inflammation. Further studies of the impact of these mutations in African Americans and on receptor function are indicated.
Project description:Increased asthma severity is not only associated with enhanced recurrent hospitalization and mortality but also with higher social costs. Several cases of asthma are atopic in nature, with the trigger for acute asthma attacks and chronic worsening of inflammation being allergens inducing an immune, IgE mediated response. Anti-inflammatory treatments are effective for most of asthma patients, but there are subjects whose disease is incompletely controlled by inhaled or systemic corticosteroids and these patients account for about 50% of the healthcare costs of asthma. Omalizumab is a biological engineered, humanized recombinant monoclonal anti-IgE antibody developed for the treatment of allergic diseases and with clear efficacy in adolescent and adult patients with severe allergic asthma. The anti-IgE antibody inhibits IgE functions blocking free serum IgE and inhibiting their binding to cellular receptors. By reducing serum IgE levels and IgE receptor expression on inflammatory cells in the context of allergic cascade, omalizumab has demonstrated to be a very useful treatment of atopic asthma, improving quality of life of patients with severe persistent allergic asthma that is inadequately controlled by currently available asthma medications. Several trials have demonstrated that this therapy is well tolerated and significantly improves symptoms and disease control, reducing asthma exacerbations and the need to use high dosage of inhaled corticosteroids.
Project description:Vitamin D insufficiency (a serum 25(OH)D <30 ng/ml) has been associated with severe asthma exacerbations, but this could be explained by underlying racial ancestry or disease severity. Little is known about vitamin D and asthma in Puerto Ricans.To examine whether vitamin D insufficiency is associated with severe asthma exacerbations in Puerto Rican children, independently of racial ancestry, atopy, and time outdoors.A cross-sectional study was conducted of 560 children ages 6-14 years with (n = 287) and without (n = 273) asthma in San Juan, Puerto Rico. We measured plasma vitamin D and estimated the percentage of African racial ancestry among participants using genome-wide genotypic data. We tested whether vitamin D insufficiency is associated with severe asthma exacerbations, lung function, or atopy (greater than or equal to one positive IgE to allergens) using logistic or linear regression. Multivariate models were adjusted for African ancestry, time outdoors, atopy, and other covariates.Vitamin D insufficiency was common in children with (44%) and without (47%) asthma. In multivariate analyses, vitamin D insufficiency was associated with higher odds of greater than or equal to one severe asthma exacerbation in the prior year (odds ratio [OR], 2.6; 95% confidence interval [CI], 1.5-4.9; P = 0.001) and atopy, and a lower FEV(1)/FVC in cases. After stratification by atopy, the magnitude of the association between vitamin D insufficiency and severe exacerbations was greater in nonatopic (OR, 6.2; 95% CI, 2-21.6; P = 0.002) than in atopic (OR, 2; 95% CI, 1-4.1; P = 0.04) cases.Vitamin D insufficiency is associated with severe asthma exacerbations in Puerto Rican children, independently of racial ancestry, atopy, or markers of disease severity or control.
Project description:Tryptase, a major secretory product of human mast cells has been implicated as a key mediator of allergic inflammation. Genetic variation in the tryptases is extensive, and α-tryptase, an allelic variant of the more extensively studied β-tryptase, is absent in substantial numbers of the general population. The degree to which α-tryptase expression may be associated with asthma has not been studied. We have investigated the α-tryptase gene copy number variation and its potential associations with phenotypes of asthma.Caucasian families (n = 341) with at least two asthmatic siblings (n = 1350) were genotyped for the α-tryptase alleles, using high-resolution melting assays. Standards for the possible α-/β-tryptase ratios were constructed by cloning α-and β-tryptase PCR products to generate artificial templates. Association analysis of asthma affection status and related phenotypes [total and allergen-specific serum IgE, bronchial hyperresponsiveness to methacholine, forced expiratory volume in 1s (FEV1 ) and atopy and asthma severity scores] was undertaken using family-based association tests (FBAT).Four consistent melting patterns for the α-tryptase genotype were identified with alleles carrying null, one or two copies of the α-tryptase allele. Possessing one copy of α-tryptase was significantly associated with lower serum levels of total and dust mite-specific IgE levels and higher FEV1 measurements, while two copies were related to higher serum concentrations of total and dust mite-specific IgE and greater atopy severity scores.Associations of α-tryptase copy number with serum IgE levels, atopy scores and bronchial function may reflect roles for tryptases in regulating IgE production and other processes in asthma.
Project description:INTRODUCTION:For patients with eosinophilic asthma with allergic characteristics, understanding the key drivers of exacerbations is important to identify optimal treatment strategies. Benralizumab is an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody that significantly reduces exacerbation frequency for patients with severe, uncontrolled eosinophilic asthma. We evaluated the predictive value of baseline blood eosinophil counts vs. serum immunoglobulin E (IgE) concentrations on exacerbation risk and the association of these variables with benralizumab treatment effect. METHODS:Analyses were performed with data pooled from the phase III SIROCCO and CALIMA benralizumab trials. Crude annual asthma exacerbation rates (AERs) were determined for placebo as a function of baseline blood eosinophil counts and serum IgE concentrations with prespecified blood eosinophil count categories (<?150, ??150 to <?300, ??300 to <?450, ??450 cells/µL) and IgE concentration quartiles (<?62.0, ??62.0 to <?176.2, ??176.2 to <?453.4, and ??453.4 kU/L). We compared AERs for patients receiving benralizumab 30 mg every 8 weeks (first three doses every 4 weeks) vs. placebo for overlapping baseline blood eosinophil count categories and serum IgE concentration quartiles via a regression approach and by continuously using locally weighted regression smoothing analysis. RESULTS:Exacerbation risk for patients with severe asthma receiving placebo increased with increasing baseline blood eosinophil counts but not with increasing serum IgE concentrations. Addition of baseline atopy status did not influence the relationship between IgE concentrations and exacerbation risk for patients receiving placebo. Patients with blood eosinophil counts ??300 cells/µL had consistent decreases in exacerbation risk with benralizumab relative to placebo across all serum IgE concentration quartiles. CONCLUSION:Baseline blood eosinophil counts, but not serum IgE concentrations, are an important predictor of exacerbation risk. Patients with severe eosinophilic asthma treated with benralizumab had consistent reductions in exacerbation risk, regardless of IgE concentrations. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov: SIROCCO, NCT01928771; CALIMA, NCT01914757.
Project description:The catalytical isoforms p110? and p110? of phosphatidylinositide 3-kinase ? (PI3K?) and PI3K? play an important role in the pathogenesis of asthma. Two key elements in allergic asthma are increased levels of eosinophils and IgE. Dual pharmacological inhibition of p110? and p110? reduces asthma-associated eosinophilic lung infiltration and ameliorates disease symptoms, whereas the absence of enzymatic activity in p110?KO?D910A mice increases IgE and basal eosinophil counts. This suggests that long-term inhibition of p110? and p110? might exacerbate asthma. Here, we analysed mice genetically deficient for both catalytical subunits (p110?/?-/-) and determined basal IgE and eosinophil levels and the immune response to ovalbumin-induced asthma. Serum concentrations of IgE, IL-5 and eosinophil numbers were significantly increased in p110?/?-/- mice compared to single knock-out and wildtype mice. However, p110?/?-/- mice were protected against OVA-induced infiltration of eosinophils, neutrophils, T and B cells into lung tissue and bronchoalveolar space. Moreover, p110?/?-/- mice, but not single knock-out mice, showed a reduced bronchial hyperresponsiveness. We conclude that increased levels of eosinophils and IgE in p110?/?-/- mice do not abolish the protective effect of p110?/?-deficiency against OVA-induced allergic airway inflammation.
Project description:BACKGROUND:The prevalence of both obesity and allergic disease has increased among children over the last several decades. Previous literature on the relationship between obesity and allergic disease has been inconsistent. It is not known whether systemic inflammation could be a factor in this relationship. OBJECTIVE:We sought to examine the association of obesity with total and allergen-specific IgE levels and allergy symptoms in US children and adolescents and to assess the role of C-reactive protein. METHODS:National Health and Nutrition Examination Survey data from 2005-2006 included measurement of total and allergen-specific IgE levels and allergy questions. Overweight was defined as the 85th or greater to less than the 95th percentile of body mass index for age, and obesity was defined as the 95th percentile or greater. Linear and logistic regression models were used to examine the association of weight categories with total IgE levels, atopy, allergen-specific IgE levels, and allergy symptoms among youth aged 2 to 19 years. RESULTS:Geometric mean total IgE levels were higher among obese (geometric mean ratio, 1.31; 95% CI, 1.10-1.57) and overweight (ratio, 1.25; 95% CI, 1.02-1.54) children than among normal-weight children. The odds ratio (OR) for atopy (any positive specific IgE measurement) was increased in the obese children compared with that seen in those of normal weight; this association was driven largely by allergic sensitization to foods (OR for atopy, 1.26 [95% CI, 1.03-1.55]; OR for food sensitization, 1.59 [95% CI, 1.28-1.98]). C-reactive protein levels were associated with total IgE levels, atopy, and food sensitization. CONCLUSIONS:Obesity might be a contributor to the increased prevalence of allergic disease in children, particularly food allergy. Systemic inflammation might play a role in the development of allergic disease.
Project description:Omalizumab is an anti-IgE monoclonal antibody (mAb) approved for the treatment of severe asthma and chronic spontaneous urticaria. Use of omalizumab is associated with reported side effects ranging from local skin inflammation at the injection site to systemic anaphylaxis. To date, the mechanisms through which omalizumab induces adverse reactions are still unknown. Here, we demonstrated that immune complexes formed between omalizumab and IgE can induce both skin inflammation and anaphylaxis through engagement of IgG receptors (Fc?Rs) in Fc?R-humanized mice. We further developed an Fc-engineered mutant version of omalizumab, and demonstrated that this mAb is equally potent as omalizumab at blocking IgE-mediated allergic reactions, but does not induce Fc?R-dependent adverse reactions. Overall, our data indicate that omalizumab can induce skin inflammation and anaphylaxis by engaging Fc?Rs, and demonstrate that Fc-engineered versions of the mAb could be used to reduce such adverse reactions.
Project description:Background:Asthma is a complex disorder with multiple phenotypes which can influence its severity and response to treatment. The TH17 lymphocytes producing IL-17A and IL17-F cytokines, may have a role on asthma inflammation. The aim of our study was to evaluate the association between genetic variants in IL17 pathway genes with asthma and atopy markers. Materials and methods:Genotyping was performed using a commercial panel in 1245 participants of SCAALA cohort. The study included 91 SNVs in IL-17 pathway genes. Logistic regressions for asthma and atopy markers were performed using PLINK 1.9. In silico analyses were performed using rSNPbase, RegulomeDB, and Gtex portal for in silico gene expression. Results and discussion:The T allele of rs1974226 in IL17A was positively associated with asthma (OR: 1.37; 95% CI 1.02-1.82). Also, the T allele of rs279548 was positively associated with asthma (OR: 1.30; 95% CI 1.02-1.64), atopy (OR: 1.62; 95% CI 1.05-2.50) and increased expression of the IL17RC in lung and whole blood tissues. The others genetic variants in the IL17 pathways genes were associated with both protection and risk for asthma development as well as with IgE levels. Conclusion:The genetic variants in IL-17-related genes are associated with the atopic asthma phenotype and IgE production.
Project description:Relationships among allergen-specific IgE levels, allergen exposure and asthma severity are poorly understood since sensitization has previously been evaluated as a dichotomous, rather than continuous characteristic.Five hundred and forty-six inner-city adolescents enrolled in the Asthma Control Evaluation study underwent exhaled nitric oxide (FE(NO)) measurement, lung function testing, and completion of a questionnaire. Allergen-specific IgE levels and blood eosinophils were quantified. Dust samples were collected from the participants' bedrooms for quantification of allergen concentrations. Participants were followed for 12 months and clinical outcomes were tracked.Among sensitized participants, allergen-specific IgE levels were correlated with the corresponding settled dust allergen levels for cockroach, dust mite, and mouse (r = 0.38, 0.34, 0.19, respectively; P < 0.0001 for cockroach and dust mite and P = 0.03 for mouse), but not cat (r = -0.02, P = 0.71). Higher cockroach-, mite-, mouse-, and cat-specific IgE levels were associated with higher FE(NO) concentrations, poorer lung function, and higher blood eosinophils. Higher cat, dust mite, and mouse allergen-specific IgE levels were also associated with an increasing risk of exacerbations or hospitalization.Allergen-specific IgE levels were correlated with allergen exposure among sensitized participants, except for cat. Allergen-specific IgE levels were also associated with more severe asthma across a range of clinical and biologic markers. Adjusting for exposure did not provide additional predictive value, suggesting that higher allergen-specific IgE levels may be indicative of both higher exposure and a greater degree of sensitization, which in turn may result in greater asthma severity.